Chromatin bridges, not micronuclei, activate cGAS after drug-induced mitotic errors in human cells

Abstract

Significance Cancer chemotherapeutic drugs that induce mitotic errors may cause tumor regression in part through the induction of interferon signaling. To test this idea, we measured the ability of antimitotic drugs with different mechanisms to activate the cGAS–STING–interferon pathway. Only microtubule stabilizers and MPS1 inhibitors activated cGAS, and this correlated with their ability to generate cGAS-coated chromatin bridges. We propose that chromatin bridges activate cGAS through a tension-dependent mechanism that depends on cytokinesis. Our results may explain the clinical failure of antimitotic drugs and help to design improved drugs. Mitotic errors can activate cyclic GMP–AMP synthase (cGAS) and induce type I interferon (IFN) signaling. Current models propose that chromosome segregation errors generate micronuclei whose rupture activates cGAS. We used a panel of antimitotic drugs to perturb mitosis in human fibroblasts and measured abnormal nuclear morphologies, cGAS localization, and IFN signaling in the subsequent interphase. Micronuclei consistently recruited cGAS without activating it. Instead, IFN signaling correlated with formation of cGAS-coated chromatin bridges that were selectively generated by microtubule stabilizers and MPS1 inhibitors. cGAS activation by chromatin bridges was suppressed by drugs that prevented cytokinesis. We confirmed cGAS activation by chromatin bridges in cancer lines that are unable to secrete IFN by measuring paracrine transfer of 2′3′-cGAMP to fibroblasts, and in mouse cells. We propose that cGAS is selectively activated by self-chromatin when it is stretched in chromatin bridges. Immunosurveillance of cells that fail mitosis, and antitumor actions of taxanes and MPS1 inhibitors, may depend on this effect.